Multi-layered surgical prosthesis

ABSTRACT

The invention relates to prostheses having a multi-layered sheet structure comprising at least two continuous polymer film layers. Also disclosed are methods of manufacturing the prostheses, as well as methods of treating a patient by implanting them into a patient. The prostheses are used in hernia repair, the repair of anatomical defects of the abdominal wall, diaphragm and chest wall, correction of defects in- the genitourinary system, and repair of traumatically damaged organs such as the spleen, liver or kidney.

FIELD OF THE INVENTION

The present invention generally relates to the field of prostheses forsurgical applications, to methods of their manufacturing and to methodsof treating a patient by implanting them into a patient. Moreparticularly, the present invention relates to prostheses having amulti-layered sheet structure and their use in hernia repair, the repairof anatomical defects of the abdominal wall, diaphragm, and chest wall,correction of defects in the genitourinary system, and repair oftraumatically damaged organs such as the spleen, liver or kidney.

BACKGROUND OF THE INVENTION

Abdominal wall repairs and especially hernia repair are among the mostcommon surgical operations in the United States. A hernia occurs whenthe inside layers of the abdominal wall weaken and then bulge or tear,causing the abdomen lining to push through the weakened area to form aballoon-like sac. The intestines or abdominal tissue slips into the sac,causing pain and risk of damage. Small hernias can be repaired withsutures but larger hernias are treated by surgically inserting meshprosthesis into the peritoneum (the membrane separating the body organsfrom the muscles and fat layers) and securing it in place with suturesor tacks. The prosthesis is usually inserted into an intra-peritoneallocation to reinforce the weakened abdominal wall to prevent the balloonsac. FIG. 1 shows an example of a hernia defect and the placement of amesh to rectify the hernia defect.

Similar mesh prostheses are commonly also used in other surgicalprocedures including the repair of anatomical defects of the severalwalls or diaphragms, correction of defects in several lumens or in thegenitourinary system, and repair of traumatically damaged organs such asinternal organs. Thereby, weakened walls can be reinforced or completedby such mesh prostheses. Sometimes, the prostheses are wound around theorgan to serve as a reinforcing member. All such prostheses are usuallymade from a textile material such as mesh fabrics of woven or knittedfibers or filaments. In the last decades, a variety of differentmaterials for the mesh fabrics have been proposed.

Polypropylene (PP) materials have widely been used in meshes for herniarepair since the 1960's. Incremental innovations were introduced alongthe way. However, to date, polypropylene has remained unsatisfactory. Ithas poor tensile strength and elongation and suffers from significantaging effects caused by the formation of microcracks in thepolypropylene material which drastically reduce its strength andflexibility over time. In the course of implantation, polypropylene alsoshows some degree of shrinkage. Polypropylene also results in frequent,significant and unacceptable connective tissue adhesion, whichinvariably leads to inflammation. The degree of tissue connectioncorrelates directly to the degree of inflammation. If the inflammationresponse is high, this may result in rigid scar plate formation.Connective tissues adhesion can also cause severe discomfort and evenmedical trauma in the patient and can lead to the necessity for apremature surgical replacement of the mesh. FIG. 2 shows examples ofsuch extensive visceral adhesions surrounding a polypropylene mesh dueto which an additional surgical treatment was necessary.

Polytetrafluoroethylene (PTFE) materials were introduced in the early1990's to separate tissue from the viscera when closing abdominalwounds. PTFE was further adopted as an enabling technology to performlaparoscopic ventral/incisional repair procedures intra-abdominally.There have been material and performance issues associated with PTFEmaterials used in hernia repair. Most PTFE materials are extruded andmade into sheets. These PTFE sheets had been implanted into the body ofa patient, i.e., seroma formation, infection, and sheet shrinkagepost-implantation. It is widely-known that a PTFE sheet shrinks onaverage 34% in 10 to 14 days post-implantation. Many of these patientshad to be an additional surgery in order to remove the implantedprosthesis due to these complications.

Recently, PVDF has been shown to be fully biocompatible and cangenerally possess high strength and flexibility, which has been shownnot to age and change over time. It also has almost no shrinkage whenused over time, and has significantly smaller tissue adhesion issues.Thus, it has been proposed as a suitable material in textile-basedmeshes for surgical applications.

In the light of the above experience with sheet-like materials, most ofthe current hernia meshes are made from filaments woven into a mesh.While easy to produce by weaving, such a process limits the designpossibilities of the mesh. For example, based on the anatomicalcharacteristics of the human abdomen, an optimally compatible meshshould have a higher degree of stretch and flexibility in one directionover the other perpendicular direction. This is not easily achievedusing a filament weaving process. Also, when stretched, such a filamentwoven mesh would undergo a reduction of pore size of its open cells orpores (the space between the filaments). It is known that such areduction of pore size would also detrimentally increase the likelihoodof visceral tissue adhesion. However, despite of these disadvantages ofwoven meshes, the common prostheses used in connection with herniarepairs are made of different textile materials such as mesh fabrics.Examples of such mesh fabrics are disclosed in US Patent Application No.2007/0250147 A1. Knitted and woven fabrics constructed from a variety ofsynthetic fibers and the use of the fabrics in surgical repair is alsoknown (e.g. U.S. Pat. No. 3,054,406).

There are two key problems still unresolved in current prosthesis suchas prosthesis for hernia repair. One is the undesired viscera tissueadhesion to the prosthesis, i.e., the adhesion of the organs inside theabdomen to the prosthesis, coming as a response to the surgicalprocedure, and inflammation caused by the prosthesis to the peritoneum.The occurrence is very high with existing prosthesis such as theabove-described hernia meshes and results in severe continuous pain,immobility and bowel related problems. Approximately above 30% of thepatients require re-surgery due to this adhesion phenomenon. The otherkey problem is that the mechanical behavior of the current prostheseschanges adversely over time due to polymer swelling and/or aging,resulting in poor flexibility and strength. Over time, the prosthesisstiffens and no longer flex in compliance to the abdominal wallmovements in any directions, causing very poor anchoring and compliance.Often, the prosthesis would completely break and need urgent surgicalreplacement.

It is therefore an object of the present invention to provide aprosthesis that overcomes some of the above explained difficulties.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, a prosthesishaving a multi-layered sheet structure is provided. The multi-layeredsheet structure comprises at least two continuous polymer film layers.

According to a further aspect of the invention, a method ofmanufacturing a prosthesis having a multi-layered sheet structure isprovided. The method comprises forming at least two continuous filmlayers to produce the multi-layered structure.

In another aspect the present invention provides a method of treating apatient in need of a sheet-like surgical prosthesis or a patient in needof hernia repair, a repair of anatomical defects of the abdominal wall,diaphragm, or chest wall, a correction of defects in the genitourinarysystem, or a repair of traumatically damaged organs such as the spleen,liver or kidney, and the like. The method includes the implantation ofthe prosthesis of the invention into the patient in need thereof.

Further embodiments are described in the dependent claims. Furtheraspects and features of the invention will also become apparent from thefollowing description of specific embodiments and non-limiting examplesof the present invention as well as from the attached drawings. It is tobe understood that the exemplified embodiments and the drawings aredesigned for the purpose of illustration only and are not intended as adefinition of the limits of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be better understood with reference to thedetailed description when considered in conjunction with thenon-limiting examples and the accompanying drawings.

FIG. 1 is an illustration of a hernia defect and a hernia repair byusing a mesh-like prosthesis, wherein FIG. 1 a shows a hernia defectresulting from a weakened abdominal wall, FIG. 1 b shows an insertedmesh placed into and fixed in the peritoneum, and FIG. 1 c shows anexploded view before closing the peritoneum.

FIG. 2 shows photos of two meshes that have adhered onto the viscera.

FIG. 3 shows a cross-sectional view of a two-layered prosthesis of theinvention comprising a porous layer 10 and a reinforcing layer 20.

FIG. 4 shows a cross-sectional view of a three-layered prosthesis of theinvention comprising a porous layer 10, a reinforcing layer 20, and ananti-adhesion coating layer 30.

FIG. 5 shows the prosthesis illustrated in FIG. 4 coated on both sideswith drug-releasing layers 40 and 42.

FIG. 6 shows another embodiment of a prosthesis comprising twomemory-effect providing layers 50 and 52 located or arranged between theporous layer 10 and the reinforcing layer 20.

FIG. 7 is a cross sectional view of an embodiment of the prosthesisshown in FIG. 3 having non-tapered through-holes extending through theprosthesis.

FIG. 8 is a cross sectional view of another embodiment of the prosthesisshown in FIG. 3 having tapered through-holes extending through theprosthesis.

FIG. 9 is a perspective view of a further embodiment of the prosthesisshown in FIG. 3 having through-holes extending through the porous layerof the prosthesis.

FIG. 10 is a perspective view of another embodiment of the prosthesisshown in FIG. 3 having through-holes extending through the porous layerof the prosthesis.

FIGS. 11 a-c are cross sectional views of three different embodiments ofthe prosthesis shown in FIG. 3, wherein the prosthesis in FIG. 11 a hasa roughed surface and the prosthesis in FIG. 11 b has a tapered poreform and the prosthesis in FIG. 11 c has a sac-like pore structure.

FIGS. 12 a-c are plane views of various embodiments of a prosthesishaving anisotropic pore shapes.

FIGS. 13 a-b are plane views of various embodiments of the prosthesis ofthe invention having anisotropic pore structures.

FIG. 14 is a sectional view of a porous layer 10 of an alternativeembodiment of the prosthesis of the invention having pores in itssurface layer in the form of wells or pot holes 60.

DETAILED DESCRIPTION OF THE INVENTION

The novel prosthesis according to the first aspect of the invention hasa multi-layered sheet structure comprising at least two continuouspolymer film layers.

The term “prosthesis” as used in the present invention means anysheet-like structure which can be a substantially flat sheet made of atleast two layers, i.e. two, three, four, five or more consecutive layersof sheet-like format, layered or arranged on each other. Such asubstantially flat sheet is often called a two-dimensional structure,even though each sheet has a specific thickness. However, the thicknessof the sheet is usually small and is generally not considered as a thirddimension. Hence, the term sheet as used to define the main structure ofthe prosthesis referred to herein is defined to be a body having a shapewhich substantially extends within a plane (two dimensions), e.g. apatch or foil. Nevertheless, the sheet structure is not limited to atwo-dimensionally one, and bodies having a three-dimensionalsub-structure with a complex shape also fall within the definition ofthe term prosthesis, if at least the main body (more than about 50% suchas 55%, 60%, 65%, 70%, 75, 80% or more of the total body) of theprosthesis has a sheet-like structure. For example, thethree-dimensional sub-structure can comprise a plug on a multi-layeredsheet made of the same or any different material. Such a plug may beused to bridge a gap between two tissues, e.g., if the wound or defectto be closed is too broad to be closed without any synthetic material ornot enough tissue is present to close the gap. Another example for sucha three-dimensional sub-structure may be an artificial opening(s), suchas a stoma or barriers isolating, e.g., blood vessels or spermatic cordsfrom adhering to the prosthesis. A further example can be a projectingguiding cone to facilitate placement of the prosthesis at the exactcenter of the abdomen using a long straight needle through the skin andhernia sac.

The prosthesis may be configured to have any suitable shape as long asit is relatively flat (i.e. extends substantially in two dimensions) andsufficiently pliable to allow a surgeon to manipulate the shape of thesurgical prosthesis to conform to the anatomical site of interest and tobe sutured or stapled thereto. The outline and the size of theprosthesis may vary according to the surgical application as would beapparent to one of skill in the art. The prosthesis can be pre-shaped orshaped by the surgeon during the surgical procedure. To be sufficientlymoldable during implantation, the prosthesis can be substantiallyflexible along its longitudinal axis (longitudinal axis in this respectmeans the main axis or the main longitudinal extension) of theprosthesis. In case of a square-like contour of the prosthesis, thelongitudinal axis, for example, can be the x or y axis, if the squarebody extends within the x-y-plane.

The prosthesis described herein can be used for implantation in mammals(such as a human, dog, cat, rabbit, mouse, rat, etc.) in need thereof.Especially, the prosthesis can be used for treating any wall defect ordamaged organ, but is not limited thereto. Various examples of walldefects are hernia defects, anatomical defects of the abdominal wall,diaphragm and/or chest wall, or defects in the genitourinary system.Various examples of damaged organs which can be treated, for example, bywinding the sheet-like prosthesis around the damaged organ or implantingit into the wall of the damaged organ for reinforcing it, includeinternal organs such as the spleen, liver, kidney, lung, bladder orheart, or organs of the intestinal tract, such as the stomach or thebowel. Illustrative examples of a prosthesis described herein are heartpatches, colonic patches, vascular prosthesis like vascular patches,patches for wound healing like suture patches or meshes, hernia patches,gastrointestinal prosthesis like prosthesis for the mouth, pharynx,esophagus, stomach, small intestine, large intestine, rectum, and anus,patches for the urogenital system and the like.

In the present context, the term “continuous polymer film layer”particularly refers to a layer made from a polymeric material in theform of a continuous film. Such a continuous film can be made by anyknown method as long as the polymer film is integrally formed or molded,i.e. formed into a one-piece film. In other words, the continuouspolymer film layer used herein is usually made from a liquid orpaste-like polymer material, followed from hardening the material togenerate a continuous polymer film in a specific form. In contrast tothe continuous film layers described herein, a woven or knitted textilemesh made of a layer of woven or knitted polymer fibers (i.e., re-shapedor transformed fibers) does not have a “continuous” polymer filmstructure as defined above. The reason is that such a textile layerincludes several distinguished filaments or fibers within the layerhaving solid/solid boundaries between each other. Thus, they do not forma continuous, integrally formed polymer film. Nevertheless, it is withinthe meaning of the term “continuous” as defined in the present inventionthat the polymer film can comprise pores or through-holes which areprepared either during the manufacturing of the polymer film layer,e.g., by casting, molding, etc., or after its manufacturing, e.g., bymechanical abrasion, cutting etc. of the hardened polymer material atthe desired region in order to form a porous or mesh-like structure.

The layer thickness of each of the layers of the multi-layered sheetstructure can be specifically adjusted in view of the respectivemechanical or physical properties of each of the layers. However, thethickness of each of the layers is generally in the micrometer range,for example, the thickness is in the range of about 1 to about 5000 μm.The layer should not be thicker than about 5000 μm, 4500 μm, 4000 μm,3500 μm, 3000 μm, 2500 μm, 2000 μm, 1500 μm, 1000 μm, 750 μm, 500 μm,400 μm, or 300 μm, however, the prosthesis should have an essentiallysheet-like shape in order to provide flexibility sufficient for theapplication in the respective treatment methods or the applications ofthe prosthesis of the invention. Especially, if the overall thickness ofthe multi-layered prosthesis will be too high, the flexibility willgenerally be so low that the prosthesis cannot be adequately anchored tothe surrounding tissue, while being able to flexibly and elasticallystretch along with the tissue. The lower limit of each of the layersshould be about 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or 100 μm in order toprovide enough burst strength to the prosthesis of the invention. Eachlayer can have a thickness in the above-mentioned range or can have avarying thickness within this range.

The polymer material can be any polymer material including oligomers(e.g., from 2 to 5 to 10 to about 25 copies of one or moreconstitutional units, commonly referred to as monomers) or homopolymersand/or copolymers (e.g., from about 25 to 50 to 100 to 250 to 500 toabout 1000 or more copies of one or more constitutional units, commonlyreferred to as monomers) of for instance a biocompatible and/orbioresorbable polymer material. The polymers may take one or morearchitectures, which may be selected, for example, from linear, cyclic,and branched including dendritic architectures, among others. Wherecopolymers are used, the at least two constitutional units can bearranged randomly, periodic, or block-like, etc.

As defined herein, a “biocompatible” polymer material refers to apolymer material with minimal toxicity or irritation to biologicaltissue. Thus, it is sufficiently tolerated by the body without adverseeffects. Such a biocompatible polymer material can be a biostablecomponent for a long-term use, i.e. a component which essentiallyremains intact over the period that the prosthesis is intended to remainimplanted in the body. A “bioresorbable” polymer material is defined tobe one which does not remain intact over the period that the prosthesisis intended to remain within the body, for example, due to dissolution,chemical breakdown, etc. of the components. In other words, abioresorbable material is readily susceptible to biological processingin vivo. It can be degraded by a living organism or a part thereof(e.g., bacterial or enzymatic action) or by the impact of the ambience,such as exposure to radiation, such as visible light, moisture, elevatedtemperature and/or air, etc. Degradation of a bioresorbable material mayresult in the formation of primary degradation products such ascompounds of low molecular weight, which then decay further through theaction of living organism. In the present context, the term“bioresorbable material” particularly refers to a material that can becompletely removed from a localized area, by physiological metabolicprocesses. A bioresorbable compound can, when taken up by a cell, bebroken down into components by cellular machinery, such as lysosomes orby hydrolysis, so that the cells can either reuse or dispose of withoutsignificant toxic effect to the cells. Examples of biodegradationprocesses include enzymatic and non-enzymatic hydrolysis, oxidation andreduction. Suitable conditions for non-enzymatic hydrolysis, forexample, include exposure of bioresorbable material to water at acertain temperature and a pH of a lysosome (i.e. the intracellularorganelle). The degradation fragments typically induce no or littleorgan or cell overload or pathological processes caused by such overloador other adverse effects in vivo.

The biocompatible polymer material which can be used in the porous layerof a prosthesis described herein is not specifically restricted and anybiocompatible material known in the art which is suitable for prosthesiscan be used. Examples for biocompatible polymer materials can include,but are not limited to, a synthetic polymer including oligomers,homopolymers, and copolymers resulting from either addition orcondensation polymerization. Various examples of suitable additionpolymers include, but are not limited to, acrylics such as thosepolymerized from methyl cerylate, methyl methacrylate, acrylic acid,methacrylic acid, acrylamide, hydroxyacrylate, hydroxyethyl acrylate,hydroxyethyl methacrylate, glyceryl acrylate, glyceryl methacrylate,methacrylamide and ethacrylamide; vinyls such as styrene, vinylchloride, polyvinyl alcohol, polyvinylidene fluoride and vinyl acetate;polymers formed of ethylene, propylene, and tetrafluoroethylene, or anypolymer blends, copolymers, or derivatives thereof. Various examples ofcondensation polymers include, but are not limited to, nylons suchpolycaprolactam or polylauryl lactam; polyurethanes, polycarbonates,polyamides, polysulfons, and poly(ethylene terephtalate). Illustrativeexamples of such biocompatible polymer materials include, but are notlimited to polyvinylidene fluoride, polyamide, polyethylene,polypropylene, poly(ethylene terephtalate), polyurethane, polystyrene,polymethacrylate, polytetrafluoroethylene, and polymers or copolymers ofp-dioxanone, trimethylene carbonate (1,3-dioxan-2-one) and alkylderivatives thereof, valerolactone, butyrolactone, decalactone,hydroxybutyrate, hydroxyvalerate, 1,5-dioxepan-2-one,1,4-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, or any polymer blendthereof.

Various examples of bioresorbable polymer materials are known in theart, any one of which is generally suitable for use in a polymer coatingdescribed herein. Examples of bioresorbable polymer materials that areconsidered bioresorbable include, but are not limited to polydioxanone,polygluconate, polylactic acid-polyethylene oxide copolymers,polysaccharides, cellulose derivatives, hyaluronic acid based polymers,polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(amino acids),aliphatic polyesters, biodegradable polyethers, poly(amino acids),copoly(ether-esters) such as PEO/PLA dextran, polyalkylenespolyoxalates, polyamides, polyketals, poly(imino carbonates),polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesterscontaining amido groups, poly(anhydrides), polcyanoacrylates, poly(alkylcyanoacrylates), poly(alkyl fumarates) like poly(propylene fumarate),polyphosphazenes, polycarbonates, naturally-occurring biodegradablepolymers such as chitosan, starch, gelatin, collagen, fibrinogen,fibrin, cellulose, alginate, polysaccharides, amylase, or any polymerblends, copolymers, or derivatives thereof.

Examples of polyorthoesters include a polyglycolide, a polylactide, apoly-co-glycolactide, a polylactic acid, a polyglycolic acid, apoly(ethylene glycolide), poly(ethylene glycol), poly(ethylene glycol)diacrylate, a polyalkylene polymer like polyethylene succinate orpolybutylene diglycolate, a polyhydroxybutyrate, polyhydroxyvalerate, apolyhydroxybutyrate/polyhydroxyvalerate copolymer, polyhydroxyalkoate, apolyanhydride, an aliphatic polycarbonate, a polycaprolactone likepoly(ε-caprolactone), a biodegradable polyamide, a biodegradablealiphatic polyester, and/or copolymers thereof. Illustrative examples ofbiodegradable polymers include, but are not limited to a polylactide,such as poly(L-lactide) (PLLA), a polycaprolactone (PCL), a copolymer ofpolycaprolactone (PCL) and polylactic acid (PLA), or a copolymer ofpoly(lactide) and poly(glycolide) (PLGA). More specific examples ofcopolymers which can be used include, but are not limited to copolymersof a poly(lactide) and a poly(glycolide) (PLGA) having an glycolidecontent of about 5-50%, 10-50%, 15-50%, or 20-50%, or approximately 20%,25%, 30%, 35%, or 50%, based on the copolymer composition. Each of theabove-mentioned bioresorbable polymer materials has a characteristicdegradation rate in the body. For example, PGA and polydioxanone arerelatively fast-bioabsorbing materials and degrade usually in the rangeof weeks to months. PLLA and polycaprolactone are examples forrelatively slow-bioabsorbing materials and degrade usually in the rangeof months to years. Thus, one skilled in the art will be able to choosean appropriate bioresorbable material with a desired degradation ratethat is suitable for the desired application of the prosthesis.

In some embodiments, a porous layer can be provided as one of the layersin the multi-layered sheet structure of the prosthesis described herein.The porous layer can be made of any one of the above-mentioned polymermaterials such as a biocompatible or bioresorbable material. A “porousstructure” refers to a layer having pores at least within the outer partor the surface area of the layer or having pores within the whole layer.“Pores” means any regular or irregular shaped pores (e.g., shortchannels or cavities (e.g., having a depth of about 10 to about 500 μm,but at least about 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 75 μm, or 100 μmand not more than about 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm,or 500 μm) in the surface area of the layer, which are also called“wells” or “pot holes”, or spherically or non-spherically shaped holeswithin the layer). Such pores or cavities in the surface layer result ina so-called “rough” surface. Roughed surface means that the surfacetexture consists of pores as defined herein. The term “pores” alsorefers to through holes (e.g., having the same depth as defined above,but which extends through the whole porous layer). Such through holescan extend from the upper surface of the porous layer to the inner partthereof in a uniform (e.g., having a cuboid or pillar-like structure),tapered (e.g., having a regular or irregular conical or step-wisetapered shape) or irregular (e.g., having a bent or meandered shape)manner. In addition, through holes may also extend not only through theporous layer, but also through two or more layers, e.g. throughout alllayers, of the prosthesis. That means that the pores may be throughholes extending within the porous layer only or extending through thewhole prosthesis, thereby forming micro-channels within the prosthesis.Generally, the extension direction of the pores or through-holes issubstantially perpendicular to the extension of the plane of the sheet.In case the through holes extend from the upper surface of theprosthesis to the opposite surface of the prosthesis, the prosthesis issometimes called to be a perforated sheet or a mesh-like sheet.

The delimiting walls of the pores or the through holes are defined by atleast a pair of opposing lateral surfaces and optionally a base surface.The term “surface” may be understood as referring to a flat or a curvedarea, which may be of any desired geometry. The distance between the twoopposing lateral surfaces of at least a portion or the entire of thepores or through holes is within the micrometer range. As used herein,the term micrometer range refers to a range of between about 1 to 10000μm. The surfaces of the pores may be of any desired internal surfacecharacteristic and any desired material as long as they allow cells ortissue of a desired type to grow therein. Various embodiments ofspecific surface characteristics include one or more steps, dents,inversions, bulges, grooves, or striations. However, in someembodiments, the surface can be of any uniform topology, for example, atleast substantially flat or at least essentially complanate, includinghaving an at least essentially straight surface.

Furthermore, different areas of the surfaces of the pores may providedifferent surface characteristics and include or consist of differentmaterials, e.g., where the pores extend within two or more differentpolymer film layers of the multi-layered structure. This allows that thetendency of the tissue to grow in or through the pores can bedifferently adjusted within one pore or through hole.

According to the invention, the pores or through-holes may have anydesired shape, including a straight, bent, or meandering (or otherwisewinding) shape and may include one or more bends, kinks or branches aslong as tissue can be grow in or grow through the pores. In typicalembodiments the pores or through holes have one longitudinal axis. Thepores may possess a cross section of any desired profile, such as beinga regular like a polygonal, cuboid (e.g. with rectangular, rhomb-like orsquare profile) or alternatively a circle-like structure or any othersuitable irregular profile having a desired irregular and/or convolutedcross section. In some embodiments the irregular profile of the pores isa profile which cannot be prepared by weaving or knitting, but which canbe manufactured by using mechanical abrading or cutting methods such asstamping, grinding, laser cutting and the like. In the context of thepresent invention, such an irregular shape like a non-circular ormonosymmetric shape is also called “anisotropic shape” of the pores orthrough-holes. “Anisotropic” in this context also means that the poreshape is irregular, e.g., non-circular or monosymmetric, or the porestructure within the layer is irregular either in the plane view or itscross-section (i.e., a monosymmetric structure which is, e.g., formed ofpores with various pore shapes or various pore sizes or pores beingnon-uniformly distributed).

In some embodiments of the invention, the pores function as means forenabling anchoring of the prosthesis to the abdominal tissues. Thisanchoring effect results from an enhanced penetration, “growth in” or“growth through” of tissue into the pores of the porous layer or theprosthesis. In addition, a porous surface can also provide a highfriction or wettability due to the higher surface area and thecapability of retaining fluids. In some embodiments, the friction of aroughed surface, which can for example be prepared by casting on aroughened mold, can for instance be suitably improved by means of atreatment for altering the surface of the pores or the porous layer.Such a treatment may include various means, such as mechanical, thermal,electrical, or chemical means. Various examples of a mechanicaltreatment suitable for adjusting the desired surface friction and/orsurface roughness of the layer include, but are not limited to, a plasmatreatment, a sandblasting treatment, an embossing treatment (e.g., byprinting a formable paste), or a sizing (or “coining”) treatment. Asexamples of electrical treatments can be given a corona treatment orelectrical discharge machining. Various examples of a chemical treatmentinclude a plasma polymerization coating, solution coating or chemicaletching. As an illustrative example of a chemical surface treatment forincreasing the wettability, it is referred to, for example, a treatmentfor rendering the surface properties of any hydrophobic surfacehydrophilic by coating with a hydrophilic polymer or by treating forinstance with surfactants like tris(hydroxymethyl)acrylaminomethane(THAM) or sucrose esters. Further examples of chemical surfacetreatments include, but are not limited to exposure to or coating withsilanes like trimethylchlorosilane, dimethyl dichlorosilane, propyltrichlorosilane, tetraethoxysilane, glycidoxy propyltrimethoxy silane,3-aminoproyl triethoxysilanepolydimethylsiloxane; polyacrylates likepoly(methyl methacrylate) or poly(ethylmethacrylate) or copolymers withother biocompatible monomers, bioresorbable polymers like poly(glycolicacid), poly(lactic acid) or poly(lactic-co-glycolic acid),adhesion-promoting molecules promoting or encouraging adhesion orattachment of endothelial cells to a surface including endothelial cellgrowth factors (e.g. platelet-derived ECGF, ECGF-β, ECGF-2a or ECGF-2b),peptides, polypeptides, glycoproteins, proteins like a cell surfaceprotein such as fibronectin, vitronectin, laminin, tenascin, collagen,gelatin, polylysine, synthetic peptides, desirably adhesion peptideshaving about 3 to about 30 amino acid residues in their amino acidsequences, such as arginine-glycine-aspartate (RGD), arginine-glutamicacid-aspartic acid-valine (REDV), andtyrosine-isoleucine-glycine-serine-arginine (YIGSR), and the like.

The pores can have any pore size as long as their size allows tissue topenetrate, “grow in” the pores or “grow through” the prosthesis duringthe healing process after the prosthesis has been inserted into apatient. In some embodiments, the average pore size of the pores in theporous layer is about 0.5 to about 5 mm, both limits inclusive. Theaverage pore size, dependent on the site of implantation and the ratioof penetration, growth in or growth through abdominal tissue into thepores. Especially, the lower limit of the average pore size can be about0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5 mm. The upper limitof the average pore size can be adjusted to any value between about 2.5to 5 mm such as about 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 4.5 mm. Theterm “average pore size” means the average value of the width ordiameter of all pores within the respective porous layer. In thisrespect, methods for measuring the average pore size are known in theart. Illustrative examples are optical microscopy or scanning electronmicroscopy, but the present invention is not limited thereto.

In some embodiments, the prosthesis having a multi-layered structure hasan additional continuous polymer film layer supporting the porous layer.In FIG. 3, an illustrative embodiment of such a two-layered prosthesisis shown in its cross-sectional view. The layer 10 is theabove-described porous layer on which the second layer 20, also calledreinforcing layer, is provided. The reinforcing layer 20 generallyprovides a respective reinforcing action to the prosthesis and, thus,allowing a reinforcement of a tissue or closing a tissue or wall defectif none of the other layers of the multi-layered structure has asufficient reinforcing action. This layer can be made of any polymermaterial as long as the material has the respective physical properties,such as a burst strength sufficient to ensure that the prosthesis doesnot break or tear after insertion into a patient and to allowreinforcement or tissue closing. Illustrative examples include, but arenot limited to, the above-described biocompatible or bioresorbablepolymer materials. In some embodiments, in which the surface of theprosthesis opposite to the porous layer, i.e. the surface facing thevisceral organs, is used as reinforcing layer, the layer can alsoprovide an anti-adhesion effect for visceral tissue to avoid anyadhesion of the prosthesis to the visceral tissue. This anti-adhesioneffect for visceral tissue can be provided for instance either by arelative smoothness of the surface of the support layer, i.e., having noessential pores or pores in the sub-micrometer range, or by comprising aspecific polymer material having anti-adhesion properties.

In the light of the above, in case the prosthesis is made of a two-layerstructure, the prosthesis is generally implanted into the body of apatient (generally a mammal) such that the outer side of the porouslayer faces the abdominal wall and the other side, i.e. the side of theabove-mentioned reinforcing layer, faces the visceral organs. Thus, themulti-layered structure of the prosthesis can enable a good anchoring tothe abdominal tissues due to the porous structure of the first layer,while the second surface which faces the visceral parts prevent visceraltissue adhesion to the prosthesis. In some embodiments, the anchoringeffect to the abdominal tissues can be improved by providing the porouslayer with a surface having a high friction or a high wettability asexplained above in more detail. In alternative embodiments, however, thesurface can be coated with an additional layer providing the respectiveproperties, i.e. a good anchoring effect to the abdominal tissues bymeans of a high surface friction and/or roughness or a high wettability,etc.

The prosthesis of the invention comprises in some embodiments anadditional polymer film layer having an anti-adhesion effect forvisceral tissues in addition to the above-described first layer enablingan anchoring property to abdominal tissues and the above-describedsecond reinforcing layer. FIG. 4 shows a cross-sectional view of anillustrative embodiment of such a three-layered prosthesis comprising aporous layer 10, a reinforcing layer 20, and an anti-adhesion coatinglayer 30. In contrast to the illustrative embodiment shown in FIG. 4,where the layer 30 covers the whole layer 20, the anti-adhesion coatinglayer 30 can be provided as part of one or both outer surface(s) of theprosthesis where the anti-adhesion effect is needed as a barrier to thesurrounding organs or tissues.

The term “anti-adhesion coating layer” means that this additional layerprovides an anti-adhesion effect to the prosthesis sufficient to preventany adhesion of organs or tissues, such as visceral tissues on theprosthesis, if a fixation of the prosthesis to these organs or tissuesis not desired. Therefore, where adhesion to visceral tissues such as inhernia repair, for example, is not desired, this layer is provided onthe side facing the visceral tissue in the body similar as in thetwo-layered embodiment described above. The anti-adhesion coating layercan generally be made of the same polymer material as the other twolayers as long as the material properties, the surface structure of thelayer or the additional components of the layer such as additives,fillers, stabilizer, anti-adhesion agents, and the like provide ananti-adhesion effect for visceral tissues. Various examples of thepolymers to be used in the anti-adhesion layer are given above.

In addition to the polymer material, the anti-adhesion coating layer maycomprise additives such as common additives or filler materials,stabilizer, or anti-adhesion agents. Any anti-adhesion agent known inthis field can be used as long as the agent is biocompatible, i.e. forinstance is non-toxic or non-irritating. Illustrative examples ofanti-adhesion agents which can be used in the anti-adhesion coatinglayer include, but are not limited to, a carboxymethyl cellulose (CMC),collagen, collage/chitosan mixtures, omega-3 fatty acid, hyaluronicacid, oxidized regenerated cellulose, dextran, pectin, gelatin,polysaccharides, biocompatible surfactants like polyethylene glycols,polypropylene glycols or poloxamers, and derivatives and/or blends fromthese materials. Collagen and CMC can be crosslinked before being usedas anti-adhesion agent.

In other illustrative embodiments, the above-described prosthesis havinga two- or three-layered structure (or a multi-layered structure withthree, four or more different layers) is constructed of at least one,two or three drug-releasing layers. That means that the porous layer 10and/or the reinforcing layer 20 and/or the anti-adhesion coating layer30 may comprise one or more releasable drugs, therapeutic agents and/orpharmaceutically active substances. In alternative embodiments, theabove-described prosthesis is coated with an additional polymericdrug-releasing layer on one or both outermost layers of the prosthesis,comprising one or more releasable drugs, therapeutic agents and/orpharmaceutically active substances. The provision of two additionaldrug-releasing layers can also be obtained if one or more of the otherlayers are drug-loaded. FIG. 5 shows an illustrative embodiment of theprosthesis shown in FIG. 4 which is coated on both sides withdrug-releasing layers 40 and 42.

In this respect, the additional drug-releasing layers 40 and 42 may bemade of any biocompatible or biodegradable polymer material as definedabove for the other layers of the multi-layered structure as long as thematerial has drug-releasing properties. For example, the polymer coatingcan control the elution of the drug, for example, by adjusting theelution or diffusion rate of the drug. The release of the drug may alsobe accomplished by controlled degradation of the polymer coating. Wherebioresorbable polymer material(s) is/are coated, the polymer coatingshould be biodegraded within the body after drug elution in order toavoid any deleterious effects which can be associated with decompositionreactions of polymer compounds in vivo. Thus, in these specificembodiments, a bioresorbable polymer material as defined above should beused for the drug releasing layers 40 and 42. In addition, the surfaceof each drug releasing layer may be surface treated in the same manneras the porous layer 10 or the anti-adhesion coating layer 30 in order tohave a similar function as the underlying layers. That means, if one orboth of the outermost drug releasing layers degrades, the underlyinglayer will have a similar anchoring or anti-adhesion effect as therespective overlying layer(s). Thus, the anchoring effect or theanti-adhesive effect of the respective surface(s) of the prosthesis willnot essentially be changed with the degradation of the drug-releasinglayer.

In the context of the present invention, the term “drug” generally meansa therapeutic or pharmaceutical agent which can be mixed into thepolymer composition of any of the above-mentioned drug-releasing layers,or impregnated or incorporated into the polymer layer in order toprovide a drug-containing polymer layer. The drug in the drug-containingcoating can be any therapeutic or pharmaceutical agent suitable for usein drug-containing layers for implantable prosthesis. Various examplesinclude, but are not limited to: anti-inflammatory agents such asadrenocortical steroids (cortisol, cortisone, corticosterone,budenoside, estrogen, sulfasalazine, mesalamine, fludrocortisone,prednisone, prednisolone, 6-alpha-methylprednisolone, triamcinolone,betamethasone, and dexamethasone), non-steroidal agents (such assalicylic acid derivatives e.g. aspirin); analgetic agents such asparacetamol (acetaminophen), non-steroidal anti-inflammatory drugs(NSAIDs) (e.g. salicylates like aspirin, ibuprofen, and naproxen),narcotic drugs (e.g. morphine), synthetic drugs with narcotic properties(e.g. tramadol); immunosuppressive or immunodepressive agents (such ascyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine,mycophenolate mofetil); wound healing or scar formation preventingagents such as angiogenic agents like vascular endothelial growth factor(VEGF), fibroblast growth factors (FGF, PDGF, TGF-β); adhesion-promotingagents promoting or encouraging adhesion or attachment of endothelialcells to a surface including endothelial cell growth factors (e.g.platelet-derived ECGF, ECGF-β, ECGF-2a or ECGF-2b); anti-microbialagents such as triclosan or cephalosporins, or an anti-microbial peptidesuch as a magainin, aminoglycoside or nitrofurantoin; cytotoxic agents,cytostatic agents or cell proliferation affectors; vasodilating agentsor agents that interfere with endogenous vasoactive mechanisms;anti-restenotic agents such as antiproliferative/antimitotic agentsincluding natural products such as vinca alkaloids (e.g. vinblastine,vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g.etoposide, teniposide), antibiotics (dactinomycin (actinomycin D),daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone,bleomycins, plicamycin (mithramycin) and mitomycin, enzymes(L-asparaginase which systemically metabolizes L-asparagine and deprivescells which do not have the capacity to synthesize their ownasparagine); antiproliferative/antimitotic alkylating agents such asnitrogen mustards (such as mechlorethamine, cyclophosphamide andanalogs, melphalan, chlorambucil), ethylenimines and methylmelamines(hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan,nirosoureas (carmustine (BCNU) and analogs, streptozocin),trazenes-dacarbazinine (DTIC); antiproliferative/antimitoticantimetabolites such as folic acid analogs (methotrexate), pyrimidineanalogs (fluorouracil, floxuridine, and cytarabine), purine analogs andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine {cladribine}); platinum coordination complexes(cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones (e.g. estrogen); anticoagulants (heparin,synthetic heparin salts and other inhibitors of thrombin); fibrinolyticagents (such as tissue plasminogen activator, streptokinase andurokinase); antiplatelet (such as aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab); antimigratory; antisecretory (such asbreveldin); para-aminophenol derivatives (e.g. acetaminophen); indoleand indene acetic acids (such as indomethacin, sulindac, and etodalac),heteroaryl acetic acids (such as tolmetin, diclofenac, and ketorolac),arylpropionic acids (such as ibuprofen and derivatives), anthranilicacids (such as mefenamic acid, and meclofenamic acid), enolic acids(such as piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (such as auranofin, aurothioglucose, goldsodium thiomalate); nitric oxide donors; anti-sense oligo nucleotidesand combinations thereof.

In some embodiments, the drug is a protein which is selected from anantibody or antibody binding fragment thereof, a growth factor such asan anti-microbial growth factor, and/or a cardiovascular therapeuticprotein. Another example of a drug that may be used in the prosthesis isa small chemical molecule selected from an anti-inflammatory agent, ananalgetic agent, an anti-microbial agent, a wound-healing or scarformation preventing agent, and/or an anti-restenotic orimmunodepressive agent.

In this context, it is noted that the drug (therapeutically orpharmaceutically active agent) to be incorporated into one or more ofthe layers of the coating can be a small organic or chemical molecule, aprotein or a fragment of the protein, a peptide or a nucleic acid suchas DNA or RNA or any combination thereof. The term “small chemicalmolecule” as used herein typically denotes an organic moleculecomprising at least two carbon atoms, but preferably not more than 7 or12 rotatable carbon bonds, having a molecular weight in the rangebetween 100 and 2000 Dalton, or between 100 and 1000 Dalton, thatoptionally can include one or two metal atoms. The term “peptide” asused herein typically refers to a dipeptide or an oligopeptide with2-about 40, 2-about 30, 2-about 20, 2-about 15, or 2-about 10 amino acidresidues. The peptide may be a naturally occurring or synthetic peptideand may comprise—besides the 20 naturally occurring L-amino acids,D-amino acids, non-naturally occurring amino acids and/or amino acidanalogs. Specific examples of synthetic peptides arearginine-glycine-aspartate (RGD), arginine-glutamic acid-asparticacid-valine (REDV), and tyrosine-isoleucine-glycine-serine-arginine(YIGSR). With “protein” is meant any naturally occurring polypeptidethat comprises more than 40 amino acid residues. The protein can be afull length protein or a truncated form, for example, an activefragment. Illustrative examples of proteins include, but are not limitedto antibodies, antibody binding fragments thereof or other bindingproteins with antibody like properties (for example, affibodies orlipocalin muteins knows as “Anticalins®”) for selected cell receptors;vascular growth inhibitors such as inhibitory antibodies, antibodiesdirected against growth factors, bifunctional molecules consisting of agrowth factor and a cytotoxin, bifunctional molecules consisting of anantibody and a cytotoxin; growth factors such as VEGF (VascularEndothelial Growth Factor) and similar factors for transmitting signals,cardiovascular therapeutic proteins or cardiac hormones and activefragments thereof or prohormones or preprohormones of such cardiachormones (these hormones or the prohormones can either be peptides asdefined herein, if they have less than 40 amino acid residues, orproteins, should their polypeptide sequence contain more the 40 aminoacid residues). Further examples for cardiovascular therapeutic agentscan be peptides or DNA such as the DNA for nitric oxide. Examples ofnucleic acid molecules include sense or anti-sense DNA molecules (ifexpression of a target gene is to be controlled) or the coding sequence(either alone or in gene-therapy vector, for example) of atherapeutically active protein that is to be produced. In such a case,the nucleic acid may code for a protein that promotes wound healing asdescribed, for example, in WO 97/47254.

The amount of the drug (or 2 or more drugs together) in one or morelayers of the coating is not limited and can be as high as wanted aslong as the physical properties of the polymer layer, especially theburst strength, the flexibility, the glass transition temperature or theelongation at break are not adversely affected. In some embodiments, theamount of the drug, based on the dry weight of the polymer layer thatcontains the drug, may be up to about 35 wt %. The drug may be presentin an amount of 0.1 to 35 wt %, 1 to 35 wt % or 1 to 10, 15, 20, 25 or30 wt % based on the dry weight of the polymer layer that contains thedrug.

In some embodiments, the prosthesis is provided with memory effectproperties. The memory effect allows the multi-layered structure toreshape itself to a desired contour (i.e., having a shape memoryeffect). The material returns from a deformed state (temporary shape) toits original (permanent) shape induced by an external stimulus, such ase.g. temperature change. This memory effect can for instance be used toplace the implant into the correct position during surgical implantationby using a minimally invasive (trough small incisions or naturalorifices) implantation technique. The prosthesis is placed at thedesired site within the body in its small temporary shape, which, afteractivating the shape memory by, e.g., temperature increase, reshapesinto its permanent (and mostly bulkier) shape. Thus, the incision canusually be made smaller or can be minimized. In addition, when memoryeffect prosthesis are used for instance in surgical sutures, the shapememory property of material used enables wound closure withself-adjusting optimal tension, which avoids tissue damage due to tootight sutures and does support healing and/or regeneration.

The memory effect properties can be provided by any of the layers 10,20, 30, 40, or 42 as discussed above, or by adding two additionalmemory-effect providing layers (50; 52) into the multi-layeredstructure. Thereby it is needless to say that these layers can beprovided as two adjacent layers or at different sites of themulti-layered structure. In an exemplary embodiment, which is shown inFIG. 6 (this is only one of various possible embodiments), the twomemory-effect providing layers 50 and 52 are, for instance, arrangedbetween the porous layer 10 and the reinforcing layer 20, which can haveat the same time anti-adhesion properties. In other examples, bothlayers can for example be provided in a three- or five-layeredprosthesis shown in FIG. 4 or 5. In order to be able to maintain therespective properties of the drug-releasing or surface-treated outermostlayers, the memory-effect providing layers 50 and 52 are usuallyprovided instead or adjacent to the reinforcing layer.

The memory-effect providing layers can be of any material having asufficient memory effect such as Shape Memory Polymers (SMPs). SMPs arepolymeric materials which have the ability to return from a deformedstate (temporary shape) to their original (permanent) shape induced byan external stimulus, such as e.g. temperature change. Various SMPs arethermoplastic and thermoset (cross-linked) shape memory polymers such aspolymers or copolymers of, e.g., polylactic acid, polyglycolic acid,polycaprolactone. Those polymers and copolymers are well-established inthe medical device technology field. Usually, the SMPs should bebiocompatible in order to avoid any toxic or irritating adverse effect.

An illustrative example for a two-layered structure having memory effectis a layer 50 made of a poly(lactide) and poly(glycolide) co-polymer(PLGA) having a poly(lactide) and a poly(glycolide) content of about50%, respectively, and a layer 52 made of a poly(lactide) andpoly(glycolide) co-polymer (PLGA) having a poly(lactide) content ofabout 75% and a poly(glycolide) content of about 25%.

In some embodiments, the prosthesis having a multi-layered sheetstructure has an anisotropic pore structure or the pores have ananisotropic shape. These anisotropic structures allow that theprosthesis of the invention can be adapted to the anisotropic nature ofa site at which the prosthesis is to be inserted. More particularly, theflexibility and burst strength of the prosthesis can be sufficiently andvariably controlled by the specific novel anisotropic pore structure toobtain improved fixation and incorporation of the prosthesis forinstance to the surrounding musculo-aponeurotic layer or the surroundingtissue.

Illustrative anisotropic structures which provide the above-mentionedadvantages and can be readily prepared by the methods of the presentinvention are shown in the FIGS. 8, 9, and 11 to 13.

FIG. 8 is a cross sectional view of an embodiment of the prosthesisshown in FIG. 3 (a two-layered prosthesis) having tapered through-holes(shown by dashed lines) extending through all layers of the prosthesis.It is needless to say that such a pore structure can be applied to allof the afore-mentioned multi-layered structures such as prosthesis withthree, four or more different layers. The cross-sectional shape of suchpores can be any regular or irregular shape such as a circular,elliptical, oval, polygonal shape (e.g. a triangular, square, pentagonalor rhomb-like shape), non-circular cross-section or a monosymmetricshape. As described above, the structure of the surfaces of the wall canalso be irregularly shaped in order to enhance the surface friction. Incontrast to the prosthesis shown in FIG. 7 having a straight shape ofthe through holes (shown by dashed lines), the penetration or growth inof tissues into the pores can be controlled by the specific anisotropicpore shape (the tapered shape, e.g. a conical or pyramidal shape). Inaddition thereto, the pore size on the surface of the reinforcing layer20 may be adjusted into a sub-micrometer range so that any tissuepenetration can be essentially prevented. The small holes on the surfaceof the reinforcing layer 20, however, can at the same time allow theelution of drugs, for example.

FIG. 9 is a perspective view of a further embodiment of the prosthesisshown in FIG. 3 (having a two-layered structure). In this exemplifiedembodiment, the pores are formed as through-holes through the porouslayer of the prosthesis only. This also facilitates the growth in ofabdominal tissues into the porous layer 10, for example, while at thesame time, the reinforcing layer 20 acts as a blocking or barrier layerfor the tissue. In this specific embodiment the pores have a square-likeshape.

FIG. 10 is a perspective view of another embodiment of the prosthesisshown in FIG. 3 also having through-holes extending through the porouslayer (10) of the prosthesis only. In this embodiment the pores have acylindrical shape.

It is to be noted here that the prosthesis of the present invention isnot limited to the two illustrative examples shown in FIGS. 9 and 10.One skilled in the art knows various shape designs in which the porescan be formed. Various illustrative examples of such pore structures(extending within the porous layer 10, but can also be extended withinone, two or more layers of the multi-layered structure or can be throughholes extending through the prosthesis) are shown in FIGS. 11 a, 11 b,and 11 c, for example. Each illustrated embodiment, such as the roughedsurface shown in FIG. 11 a having cavities or depressions in the surfacearea only, the tapered pore form shown in FIG. 11 b having a conical orpyramidal shape, for example, or the sac-like pore shape shown in FIG.11 c is suitable for providing a controlled anisotropic pore structureto ensure a better fixation and incorporation of the prosthesis forinstance to the surrounding musculo-aponeurotic layer or the surroundingtissue. One skilled in the art can find additional pore anisotropic poreshapes by routine experimentation.

FIGS. 12 a-c and 13 a-b show further illustrative embodiments of aprosthesis having an improved anisotropic pore shape or pore structure.FIGS. 12 a-c are plane views of various embodiments of a prosthesishaving anisotropic pore shapes. FIGS. 13 a-b are plane views of variousembodiments of a prosthesis having anisotropic pore structures. Forexample in FIG. 13 a, the pores on the left side of the prosthesis havea square shape, while the pores on the right side have a rhomb-likeshape, while the longitudinal axis has not been changed. Similarly, thepore shape changes from the left side to the right side in theprosthesis shown in FIG. 13 b. In this embodiment, the shape varies froma circular one to an oval shape. Several possibilities of varying theshape of coplanar pores or mixing different shapes can be made by oneskilled in the art by routine experimentation in order to design aspecific controlled pore structure having anisotropy sufficient tobetter copy or simulate the anisotropic anatomical nature of thesurrounding tissue.

It is noted that all these pore shapes cannot be made by any weaving orknitting technique as described in the prior art discussed above, sothat these specific novel anisotropic pore shapes and their effects onthe anisotropy of the prosthesis are unique in the art in the field ofsurgical prosthesis.

An alternative embodiment is shown in FIG. 14. In this embodiment aporous layer 10 comprising pores in its surface layer in the form ofwells or pot holes 60 is shown. The other layers like a reinforcinglayer 20 etc. are not shown in this figure. The film thickness of theporous layer is, e.g., about 500 μm, and wells or pot holes 60 can becut into the porous layer, e.g., by using laser cutting, embossing, ordrilling. In this case, the wells or pot holes 60 do not penetrate theporous layer because the depth of the holes 60 is less than thethickness of the porous layer. In the embodiment shown in FIG. 14, thethickness is, e.g., about 300 μm. In other parts of the prosthesis inwhich no wells or pot holes 60 are provided, pores such as trough holesperforating the porous layer or the whole prosthesis can be provided(not shown in the Figure) as described above. Thus, the prosthesis ofthis embodiment can have two different pores, namely the through holesand the holes 60. The holes 60, i.e., the wells or pot holes, can beused to induce cell regeneration, for example. In order to induce cellregeneration, the wells or pot holes can contain additives such asdrugs, proteins etc. as described above or they can simply act as cavitysites for cell regeneration.

In the second aspect of the invention, a method of manufacturing aprosthesis having a multi-layered sheet structure is provided. Themethod comprises steps of forming two continuous polymer film layers toproduce the multi-layered sheet structure.

In this respect, it is reminded that any layer of the prosthesis is madefrom a polymeric material in the form of a continuous film. Furthermore,the continuous polymer film layer is usually made from a liquid orpaste-like polymer material, followed from hardening the material inorder to generate a continuous polymer film. In some embodiments, the atleast two layers are formed, for example, by molding methods likeinjection molding and compression molding; coating methods like solutioncoating, dip coating or spin coating; solution casting; and/or anextrusion method like blow extrusion or film extrusion.

In case a casting method is used, the polymer film can be interrupted bypores or through-holes during the manufacturing of the polymer filmlayer by using a specific mold having matrix pattern for the pores. Forexample, a roughed surface can be provided by using a roughened mold.Similarly, any pore structure such as a mesh-like structure can beeasily made by injection molding techniques if a respective two-part ormulti-part mold is used.

In alternative embodiments, various mechanical or chemical treatmentscan be used for treating the multi-layered structure or one, two or moreof these layers or the surface of the outermost layers. Exemplaryembodiments of mechanical treatments are mechanical abrading or cuttingmethods, such as stamping, grinding, laser cutting, electrical dischargemachining, drilling and the like. By these methods the respectivepolymer layers treated at the desired region can easily be formed into aporous or mesh-like structure.

In another exemplary embodiment, the friction of a roughed surface,which can for example be prepared by casting on a roughened mold,followed by layering the other layers of the multi-layered structurethereon, can for instance be suitably adjusted by means of a treatmentfor altering the surface of the pores or the porous layer. Such atreatment may include various means, such as mechanical, thermal,electrical, or chemical means. Various examples of a mechanicaltreatment suitable for adjusting the desired surface friction and/orsurface roughness of the layer include, but are not limited to, a plasmatreatment, a sandblasting treatment, an embossing treatment, or a sizingtreatment. Various examples of a chemical treatment include a plasmapolymerization coating or solution coating or a chemically etchingtreatment. As an illustrative example of a chemical surface treatmentfor increasing the wetting ability, for example, can be mentioned atreatment for rendering the surface properties of any hydrophobicsurface hydrophilic by coating with a hydrophilic polymer or by treatingfor instance with surfactants.

The above-described solvent cast multi layered film process helps toovercome the limitations of the current filament woven mesh processes asthe film will after its manufacturing be laser cut. Laser cutting opensup all possibilities of designs including the anisotropic design thatwould optimally match the anisotropic anatomical nature of the abdominalwall. Thus, the prosthesis generally is cut from a flat multilayeredsheet by laser cutting, using a design which has been computationallyanalyzed (e.g., by Finite Element Analysis, FEA; generally using aniterative process) beforehand to give the anisotropic propertiesdesired. The same method can also be used to achieve a design using aminimal amount of materials. Therefore, material costs can be loweredand the manufacturing process can be made more cost efficient. Inaddition, in line with the so-called Halstead's principle, the leastamount of foreign body introduced to patients, the better they are. Inhernia repair, it equates to having the least amount of material withoptimum strength for permanent support. Using this principle, the designof the pores and the thickness of the prosthesis can satisfactorily beadjusted by the above-described method.

All these methods easily allow the fabrication of a controlled porestructure. For example, pores having an irregular shape like anon-circular or monosymmetric shape or pore structures with ananisotropic structure can be manufactured by these methods. It isneedless to say that regular pore structures can also be manufactured bythese methods. Since the different pore shapes have already beendescribed in detail with respect to the prosthesis it will not berepeated here. One skilled in the art knows how to produce therespective shape by using one of the above-mentioned methods.

In another exemplified embodiment, the outermost layer of amulti-layered structure is made by dispersing inorganic or organic fineparticles and/or inorganic/organic composite particles in the polymermixture and then molding the respective layer to obtain a roughenedsurface. Various examples include, for example, inorganic particles suchas silica, titania, bentonite, clays or mixtures thereof; organicparticles such as oligomers or polymers having a melting point higherthan the polymer of the polymeric film; or inorganic/organic compositeparticles such as particles of silica or titania as core material andhaving a polymeric shell. Thus, a roughed surface having improvedsurface friction properties can be provided. If needed, the obtainedrough surface can be after-treated as described above in order tofurther improve the friction or wettability of the surface.

As described above, the method comprises in exemplary embodiments theforming of an anti-adhesion coating layer on at least a part of one orboth outer surface(s) of the prosthesis, where the respective coating isdesired. The method can also encompass the step of providing drugreleasing layer(s) or memory effect-providing layers.

In the following, illustrative working examples of manufacturing methodsof a multi-layer prosthesis are described, wherein these examples arenot intended to limit the present invention to these three embodiments.In all examples polyvinylidene fluoride (PVDF) is used as polymermaterial of the multi-layered prostheses. The Applicant has developedthese novel methods to cast multiple layers of PVDF which has been shownto be fully biocompatible. PVDF has higher strength and yet retains goodflexibility. This allows the prosthesis to be made thinner than currentpolypropylene mesh prostheses. It also retains these properties verywell and does not form cracks over time when embedded in the body, whichwere the key problems in polypropylene mesh. It is highly resistant tohydrolysis and has minimal shrinkage. This is a further strongimprovement over a conventional PTFE mesh.

(1) Solution Casting:

According to this method the polymer material was first dissolved into asuitable solvent. In those layers containing drugs, drugs were firstdissolved in the polymer solution before being casted. The solution wasthen applied onto a mold where the surface profile determined thesurface roughness or profile of the first layer. The contour of the moldwas also the shape of the final desired contour when the film has beenimplanted. The layer was then dried carefully to release all thesolvents before the next layer was similarly deposited. This process wasrepeated iteratively until the desired number of layers had beenachieved. The whole multi layered film was then heat treated above glasstransition temperature of one or more polymer layers on the mold toobtain the formation of a prosthesis in the desired shape. The contouredfilm was then flattened at 25° C. or below into a flat sheet beforeinsertion into the body. The film will then revert to its desiredcontoured shape at 37° C. once placed into the body.

(2) Dip Coating:

The multi layered film was casted by dip-coating the mold vertically andin a controlled manner into a solution of a polymer and lifting it upwith the polymer layer coating on the mold. In those layers the drugswere first dissolved in the polymer solution before being casted. Thecoating was then dried to release all the solvents before dip coatinginto another polymer solution to achieve the second layer. The processwas then repeated iteratively until the desired layers had beenobtained. The mold had a surface profile determining the surfaceroughness or profile of the first layer. The contour of the moldresembled the shape of the final desired contour obtained afterimplantation of the film. The whole multi layered film was then heattreated above glass transition temperature of one or more polymer layerson the mold to obtain the formation of the desired shape. The contouredfilm was then flattened at 25° C. or below into a flat sheet beforeinsertion into the body. The film will then revert to its desiredcontoured shape at 37° C. once placed into the body.

(3) Spin Coating:

Spin coating employs a method where the polymer solution is applied dropby drop on a fast spinning mold to obtain an even spun coating on themold. This method was used for the desired polymer materials. In thoselayers containing drugs, drugs were first dissolved in the polymersolution before being casted. The contour of the mold also resembled theshape of the final desired contour obtained after implantation of thefilm. The layer was then dried carefully to release all the solventsbefore the next layer was deposited on the previous layer in the samemanner. This process was repeated iteratively until the desired numberof layers had been achieved. The whole multi layered film was then heattreated above glass transition temperature of one or more polymer layerson the mold to obtain the desired shape. The contoured film was thenflattened at 25° C. or below into a flat sheet before insertion into thebody. The film will then revert to its desired contoured shape at 37° C.once placed into the body.

(4) Alternative Manufacturing Methods:

Similar PVDF films were prepared by molding or extrusion methods insteadof the above-described casting methods. After having molded the film, aspecific pore pattern was cut by using laser cutting or mechanicallycutting (e.g., drilling), thus providing a mesh-like film structure.

The thus obtained film structure was then further processed by adheringa top coating made of carboxymethylcellulose (other biodegradablematerials can also be used in the same manner) containingpharmaceutically active agents thereon. In order to enhance the adhesiveproperties, biocompatible polymers like PLGA were used asadhesive-promoting agents in the form of an additional film or asadjective to the carboxymethylcellulose. Thus, a multi-layered filmprosthesis was prepared comprising a porous PVDF film layer.

Another aspect of the invention refers to methods of treating a patientby implanting the prosthesis according to the present invention. Themethod according to the third aspect of the invention generallyencompasses the step of implanting the prosthesis of the invention asdescribed beforehand into a mammal such as a human, dog, cat, rabbit,mouse, rat, etc.

In some embodiments, the method (or the prosthesis) can be used fortreating any wall defect or damaged organ, but is not limited thereto.Various examples of wall defects are hernia defects, anatomical defectsof the abdominal wall, diaphragm and/or chest wall, or defects in thegenitourinary system. Various examples of damaged organs which can betreated, for example, by winding the sheet-like prosthesis around thedamaged organ or implanting it into the wall of the damaged organ forreinforcing it, include internal organs such as the spleen, liver,kidney, lung, bladder or heart, or organs of the intestinal tract suchas the stomach or the bowel. Illustrative examples of the method includethe implantation of a prosthesis, such as heart patches, colonicpatches, vascular prosthesis like vascular patches, patches for woundhealing like suture patches or meshes, hernia patches, gastrointestinalprosthesis like prosthesis for the mouth, pharynx, esophagus, stomach,small intestine, large intestine, rectum, and anus, patches for theurogenital system and the like.

In conclusion, it has been shown by the above description that aprosthesis can be made perfectly compliant with the surrounding tissueand move in line with these tissues. In addition, a prosthesis canadequately anchor to the surrounding tissue and be able to flexibly andelastically stretch along with the tissue due to their unique porestructure, especially the anisotropic pores or anisotropic porestructures. Therefore, the novel prostheses can overcome most of thedisadvantages of the conventional prostheses, which generally would notanchor well or are not flexible (such as the conventional hernia meshesmade of several polymeric filaments or fibers) and, thus, slidepainfully against the patient abdominal tissues. This sliding generallycauses great discomfort and even trauma against the abdomen.

In addition, the prosthesis of the invention do not allow itself todevelop tissue adhesions with the viscera because of the possibility ofproviding each layer of the multi-layered structure with differentproperties such as an anti-adhesion property of the layer facing thevisceral tissue. Since visceral adhesions generally result inpostoperative pain, intestinal obstruction, and most seriously, fistulaformation, the novel prosthesis of the present invention overcome thesedisadvantages of the conventional prosthesis at the same time.

Moreover, the present invention provides a novel drug-releasingmulti-layer prosthesis for, e.g., reinforcement of abdominal wall inmammals or repairing other defects in walls or organs. To avoidunintended connection to visceral tissue or internal organs a prosthesisis provided in which one side of the prosthesis comprises a non-adhesivefunction and the other side comprises a higher friction and adhesivefunction to promote anchoring of the prosthesis to tissue or organsurfaces. This prosthesis can also be used in other surgical proceduresincluding the repair of anatomical defects of the abdominal wall,diaphragm, and chest wall, correction of defects in the genitourinarysystem, and repair of traumatically damaged organs such as the spleen,liver or kidney.

1. A prosthesis having a multi-layered sheet structure comprising atleast two continuous polymer film layers, wherein the at least twocontinuous polymer film layers are integrally formed with nodistinguished filaments or fibers within each layer, wherein the atleast two continuous polymer film layers are in continuous contact witheach other to form the multi-layered sheet structure.
 2. The prosthesisaccording to claim 1, wherein at least one layer of the multi-layeredstructure is a porous layer having pores.
 3. The prosthesis according toclaim 2, wherein the pores extend from one surface of the porous layerto the second surface of the porous layer to form through-holes in theporous layer.
 4. The prosthesis according to claim 2, wherein the poresextend from one surface of the prosthesis to the other surface of theprosthesis to form through-holes in the multi-layered structure of theprosthesis.
 5. The prosthesis according to claim 2, wherein the porouslayer has a high friction to enable a good anchoring to abdominaltissues.
 6. The prosthesis according to claim 2, wherein the porouslayer has a high wetting ability to enable anchoring to abdominaltissues.
 7. The prosthesis according to claim 2, wherein the surfaceopposite to the surface of the porous layer has an anti-adhesion effectfor visceral tissue.
 8. The prosthesis according to claim 1,additionally comprising an anti-adhesion coating layer on at least apart of one or both outer surface(s) of the prosthesis.
 9. Theprosthesis according to claim 8, wherein the anti-adhesion coating layercomprises a biocompatible or bioresorbable polymer.
 10. The prosthesisaccording to claim 8, wherein the anti-adhesion coating layer comprisesan anti-adhesion agent.
 11. The prosthesis according to claim 10,wherein the anti-adhesion agent is a carboxymethyl cellulose, collagen,omega-3 fatty acid, hyaluronic acid, oxidized regenerated cellulose,gelatin, polysaccharides, biocompatible surfactants like polyethyleneglycols, polypropylene glycols or poloxamers, and derivatives and/orblends from these materials.
 12. The prosthesis according to claim 1,wherein each of the layers of the multi-layered structure comprises abiocompatible or bioresorbable polymer material.
 13. The prosthesisaccording to claim 9, wherein the biocompatible polymer material is anyof polyvinylidene fluoride, polyamide, polyethylene, polypropylene,poly(ethylene terephtalate), polyurethane, polystyrene,polymethacrylate, polytetrafluoroethylene, and polymers or copolymers ofp-dioxanone, trimethylene carbonate (1,3-dioxan-2-one) and alkylderivatives thereof, valerolactone, butyrolactone, decalactone,hydroxybutyrate, hydroxyvalerate, 1,5-dioxepan-2-one,1,4-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one or any polymer blendthereof.
 14. The prosthesis according to claim 9, wherein thebioresorbable polymer material is any of polyglycolide, polylactide andpoly-co-glycolactide, polylactic acid, polyglycolic acid, poly(ethyleneglycolide), polyethylene glycol, polycaprolactone likepoly(ε-caprolactone), polydioxanone, polygluconate, polylacticacid-polyethylene oxide copolymers, polysaccharides, cellulosederivatives, hyaluronic acid based polymers, starch, gelatin, collagen,polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(amino acids)or any polymer blends, copolymers, or derivatives thereof.
 15. Theprosthesis according to claim 2, wherein the pores have an average poresize of about 0.5-5 mm.
 16. The prosthesis according to claim 2 whereinthe pores have an average pore size of about 1-4 mm.
 17. The prosthesisaccording to claim 2, wherein the pores have a regular or irregularshape.
 18. The prosthesis according to claim 17, wherein the poreshaving a regular shape have a circular, elliptical, oval or polygonalshape such as a triangular, square, pentagonal or rhomb-like shape. 19.The prosthesis according to claim 17, wherein the pores having anirregular shape have a non-circular cross-section or a monosymmetricshape to provide an anisotropic pore structure.
 20. The prosthesisaccording to claim 17, wherein coplanar pores in the multi-layeredstructure have different pore diameters or pore shapes to provide ananisotropic pore structure.
 21. The prosthesis according to claim 2,wherein the pores have an anisotropic shape in its cross-section. 22.The prosthesis according to claim 21, wherein the anisotropic shape ofthe pores tapers from the upper surface of the porous layer to the innerpart thereof or the opposite side of the prosthesis.
 23. The prosthesisaccording to claim 19, wherein the anisotropic pore structure or theanisotropic shape of the pores is adapted to the anisotropic anatomicalnature of a site at which the prosthesis is to be inserted in a patient.24. The prosthesis according to claim 1, wherein one, two, or more ofthe layers of the multi-layered structure like the porous layer or theanti-adhesion coating layer are drug-releasing layers comprising one ormore releasable drugs, therapeutic agents and/or pharmaceutically activesubstances.
 25. The prosthesis according to claim 1, further comprisingan additional polymeric drug-releasing layer on one or both outermostlayers of the prosthesis, comprising one or more releasable drugs,therapeutic agents and/or pharmaceutically active substances.
 26. Theprosthesis according to claim 24, wherein the drug is selected from thegroup consisting of a small chemical molecule, a peptide, a protein anucleic acid or any combination thereof.
 27. The prosthesis according toclaim 26, wherein the protein is selected from an antibody or antibodybinding fragment thereof, a growth factor such as an anti-microbialgrowth factor, and/or a cardiovascular therapeutic protein.
 28. Theprosthesis according to claim 26 wherein the small chemical molecule isselected from an anti-inflammatory agent, an analgetic agent, ananti-microbial agent, a wound-healing or scar formation preventingagent, and/or an anti-restenotic or immunodepressive agent.
 29. Theprosthesis according to claim 1, wherein the prosthesis has memoryeffect properties.
 30. The prosthesis according to claim 29 comprisingtwo additional layers providing the memory effect properties in itsmulti-layered sheet structure.
 31. The prosthesis according to claim 1,wherein the multi-layered sheet structure is substantially flexiblealong the longitudinal axis of the sheet structure.
 32. The prosthesisaccording to claim 1, wherein the multi-layered sheet structurecomprises at least two different pore structures wherein the first porestructure comprises through holes through the porous layer or throughthe prosthesis and the second pores structure comprises one or morewells or pot holes on those parts of the porous layer where the firstpore structure is not provided, wherein the depth of the wells or potholes is smaller as the thickness of the porous layer.
 33. A method ofmanufacturing a prosthesis having a multi-layered sheet structure,comprising integrally forming at least two continuous polymer filmlayers with no distinguished filaments or fibers within each layer,wherein the at least two continuous polymer film layers are incontinuous contact with each other to produce the multi-layered sheetstructure.
 34. The method according to claim 33, wherein the at leasttwo layers are formed by molding methods like injection molding andcompression molding; coating methods like dip coating or spin coating;solution casting; and/or an extrusion method like blow extrusion or filmextrusion.
 35. The method according to 33, wherein the outermost layerof the multi-layered sheet structure is formed by casting the polymer ona roughened mold to obtain a roughed surface, forming the additionallayers thereon and, then, mechanically or chemically treating saidroughed surface of the porous layer to increase its surface friction andwetting ability.
 36. The method according to claim 35, wherein themechanical treatment of the roughed surface includes a plasma treatment,a sandblasting treatment, an embossing treatment, or a sizing treatment.37. The method according to claim 35, wherein the chemical treatment ofthe roughed surface comprises an etching treatment or a coating like aplasma polymerization coating or solution coating.
 38. The methodaccording to claim 33, wherein the outermost layer of the multi-layeredstructure is made by dispersing inorganic or organic fine particlesand/or inorganic/organic composite particles in the polymer mixture andthen molding the respective layer to obtain a roughened surface.
 39. Themethod according to claim 38, wherein the inorganic particles includesilica, titania, bentonite, clays or mixtures thereof.
 40. The methodaccording to claim 38, wherein the organic particles include oligomersor polymers having a melting point higher than the polymer of thepolymeric film.
 41. The method according to claim 38, wherein theinorganic/organic composite particles include particles of silica ortitania in the core and a polymeric shell.
 42. The method according toclaim 33, wherein pores are made in one or more layers of themulti-layered structure by using a matrix having a pore pattern.
 43. Themethod according to claim 33, wherein a porous layer is formed in theform of a solid layer as an outermost layer and then the porousstructure is formed from this solid layer by means of a mechanicaltreatment.
 44. The method of claim 43, wherein the mechanical treatmentis a grinding process, a laser cutting process, an electrical dischargemachining, stamping or a mechanical abrading process.
 45. The methodaccording to claim 33, wherein an anti-adhesion coating layer is formedon at least a part of one or both outer surface(s) of the prosthesis.46. The method according to claim 45, wherein the anti-adhesion coatinglayer comprises a biocompatible or bioresorbable polymer.
 47. The methodaccording to claim 45, wherein the anti-adhesion coating layer comprisesan anti-adhesion agent.
 48. The method according to claim 33, whereinthe multi-layered structure is made of at least two layers comprising abiocompatible or bioresorbable polymer material.
 49. The methodaccording to claim 46, wherein the biocompatible polymer material is anyof polyvinylidene fluoride, polyamide, polyethylene, polypropylene,poly(ethylene terephtalate), polyurethane, polystyrene,polymethacrylate, polytetrafluoroethylene, and polymers or copolymers ofp-dioxanone, trimethylene carbonate and alkyl derivatives thereof,valerolactone, butyrolactone, decalactone, hydroxybutyrate,hydroxyvalerate, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one,6,6-dimethyl-1,4-dioxan-2-one or any polymer blend thereof.
 50. Themethod according to claim 46, wherein the bioresorbable polymer materialis any of polyglycolide, polylactide and poly-co-glycolactide,polylactic acid, polyglycolic acid, poly(ethylene glycolide),polyethylene glycol, polycaprolactone like poly(ε-caprolactone),polydioxanone, polygluconate, polylactic acid-polyethylene oxidecopolymers, polysaccharides, cellulose derivatives, hyaluronic acidbased polymers, starch, gelatin, collagen, polyhydroxybutyrate,polyanhydride, polyphosphoester, poly(amino acids) or any polymerblends, copolymers, or derivatives.
 51. The method according to claim33, wherein at least one layer is provided with pores having an averagepore size of about 0.5-5 mm.
 52. The method according to claim 33,wherein at least one layer is provided with pores having an average poresize of about 1-4 mm.
 53. The method according to claim 33, wherein atleast one layer is provided with pores having a regular or irregularshape.
 54. The method according to claim 53, wherein the pores having aregular shape have a circular, elliptical, oval or polygonal shape suchas a triangular, square, pentagonal or rhomb-like shape.
 55. The methodaccording to claim 53, wherein the pores having an irregular shape havea non-circular cross-section or a monosymmetric shape to provide ananisotropic pore structure.
 56. The method according to claim 53,wherein coplanar pores in the multi-layered structure have differentpore diameters or pore shapes to provide an anisotropic pore structure.57. The method according to claim 33, wherein at least one layer isprovided with pores having an anisotropic shape in its cross-section.58. The method according to claim 57, wherein the anisotropic shape ofthe pores tapers from the upper surface of the porous layer to the innerpart thereof or the opposite side of the prosthesis.
 59. The methodaccording to claim 53, wherein the anisotropic pore structure or theanisotropic shape of the pores is adapted to the anisotropic anatomicalnature of a site at which the prosthesis is to be inserted in a patient.60. The method according to claim 33, wherein one, two, or more of thelayers of the multi-layered structure like the porous layer or theanti-adhesion coating layer are made as drug-releasing layers by addingone or more releasable drugs, therapeutic agents and/or pharmaceuticallyactive substances in the respective layers before molding the layers orby impregnating them into the molded layers.
 61. The method according toclaim 33, further comprising the step of forming an additional polymericdrug-releasing layer on one or both outermost layers of the prosthesis,comprising one or more releasable drugs, therapeutic agents and/orpharmaceutically active substances.
 62. The method according to claim33, wherein two layers in the multi-layered sheet structure are formedto provide a memory effect.
 63. The method according to claim 62,wherein these two layers are formed of a polymeric material as twoadditional layers providing the memory effect properties in themulti-layered sheet structure of the prosthesis.
 64. A method oftreating a patient by implanting the prosthesis according to claim 1.65. The method according to claim 64, wherein the prosthesis isimplanted for strengthening abdominal wall hernia defects.
 66. Themethod according to claim 64, wherein the prosthesis is implanted forrepairing an anatomical defect of the abdominal wall, diaphragm and/orchest wall.
 67. The method according to claim 64, wherein the prosthesisis implanted for correction of defects in the genitourinary system. 68.The method according to claim 64, wherein the prosthesis is implantedfor repairing traumatically damaged organs such as the spleen, liver,kidney, lung, bladder or heart.